Method for producing crystal of uracil compound

ABSTRACT

in organic solvents consisting of a C3-C6 alcohol solvent and an aromatic solvent to obtain a solution, and precipitating a crystal of said uracil compound from the solution.

TECHNICAL FIELD

This application claims priorities to and the benefits of JapanesePatent Application Nos. 2016-140053 filed on Jul. 15, 2016, 2016-248827filed on Dec. 22, 2016, and 2017-055556 filed on Mar. 22, 2017, theentire contents of which are incorporated herein by reference.

The present invention relates to a method for producing a crystalcomprising a uracil compound which is an active ingredient of anherbicide.

BACKGROUND ART

The uracil compound represented by the following formula (1)(hereinafter referred to as “present uracil compound”) is known as anactive ingredient of an herbicide (Patent Literature 1; compounds 7 to8). Further, it is described that the present uracil compound isproduced by a multistep reaction process (see Patent Literatures 1 to 5etc.)

CITATION LIST Patent Literature

-   [Patent Literature 1] JP 2002-155061 A-   [Patent Literature 2] JP 2003-48885 A-   [Patent Literature 3] JP 2003-286284 A-   [Patent Literature 4] JP 2003-286285 A-   [Patent Literature 5] JP 2003-321468 A

SUMMARY OF INVENTION Technical Problem

When an organic compound such as an agrochemical active ingredient isproduced in an industrial scale by a multistep reaction process, it isimportant to establish a purification method to obtain a final compoundwith high purity.

An object of the present invention is to provide a method for producinga crystal of the present uracil compound with high purity by a processwhich can be carried out in an industrial scale.

Solution to Problem

The present inventors have intensively studied to find out a method forproducing the present uracil compound represented by formula (1)

with high purity. As a result, they have found out that a crystal of thepresent uracil compound can be obtained with high purity by dissolving acomposition comprising the present uracil compound (said composition maycomprise the present uracil compound with an arbitrary purity; andhereinafter said composition is referred to as “crude uracilcomposition”) in solvents comprising specific organic solvents, and thenprecipitating a crystal, to complete the present invention.

That is, a method for producing a crystal of the present uracil compoundof the present invention includes the followings:

[1] A method for producing a crystal of the present uracil compoundcharacterized in that the method comprises dissolving a crude uracilcomposition in organic solvents consisting of a C3-C6 alcohol solventand an aromatic solvent to obtain a solution, and precipitating acrystal of the present uracil compound from the solution.[2] The method for producing a crystal of the present uracil compoundaccording to [1], wherein the crystal of the present uracil compound isprecipitated by cooling a solution of a crude uracil composition.[3] The method for producing a crystal of the present uracil compoundaccording to [1] or [2], wherein

the C3-06 alcohol solvent is a solvent selected from the groupconsisting of 1-propanol, 2-propanol, 1-butanol, 2-butanol,2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol,3-methyl-1-butanol, and 2-methyl-2-butanol, or a mixture of two or moreof them, and

the aromatic solvent is a solvent selected from the group consisting oftoluene, o-xylene, m-xylene, p-xylene, ethylbenzene, and chlorobenzene,or a mixture of two or more of them.

[4] The method for producing a crystal of the present uracil compoundaccording to [1], [2], or [3], wherein a weight ratio of the C3-06alcohol solvent to the aromatic solvent is 50:50 to 98:2.

Advantageous Effects of Invention

The present invention provides a method for producing a crystal of thepresent uracil compound with high purity, wherein the present uracilcompound is the final compound produced by a multistep reaction process.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 A FIGURE showing an example of powder X-ray diffraction ofcrystals of the present uracil compound obtained by the productionmethod of the present invention.

DESCRIPTION OF EMBODIMENTS

In the mixture consisting of two types of organic solvent used in thepresent invention, one solvent is a C3-C6 alcohol solvent (hereinafterreferred to as “Solvent A”), and the other solvent is an aromaticsolvent (hereinafter referred to as “Solvent B”).

Solvent A is a solvent represented by formula ROH (wherein R is a C3-C6hydrocarbon group), and specific examples of Solvent A include alcoholsolvents such as 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol,2-butanol (sec-butyl alcohol), 2-methyl-1-propanol (isobutyl alcohol),2-methyl-2-propanol (tert-butyl alcohol), 1-pentanol, 3-methyl-1-butanol(isoamyl alcohol), 2-methyl-2-butanol (tert-amyl alcohol), 1-hexanol,and cyclohexanol.

Solvent B is a solvent which is benzene optionally substituted with oneor more halogen atoms (for example, chlorine atoms) or one or more C1-C3aliphatic hydrocarbon groups optionally substituted with said one ormore halogen atoms, and preferably benzene optionally substituted withone or more C1-C3 aliphatic hydrocarbon groups or one or more chlorineatoms, and specific examples of Solvent B include aromatic solvents suchas benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene,propylbenzene, isopropylbenzene, 1,3,5-trimethylbenzene (mesitylene),1,2,4-trimethylbenzene (pseudocumene), chlorobenzene, o-dichlorobenzene,m-dichlorobenzene, and p-dichlorobenzene.

The present uracil compound used in the production method of the presentinvention can be produced by, for example, any one of the followingscheme (2) to scheme (5).

In the scheme (2) to scheme (5), the compound represented by formula(A1) (hereinafter referred to as “Compound (A1)”) and the compoundrepresented by formula (A11) (hereinafter referred to as “Compound(A11)”) are described in JP 2002-363170 A or WO 2007/083090 pamphletetc., and can be produced by a method described in said literatures.

The crude uracil composition comprises 60 to 97% by weight of thepresent uracil compound, and also comprises a compound such as aproduction intermediate in the scheme (2) to scheme (5) and a derivativederived from said production intermediate etc. (hereinafter referred toas “present contaminating compound”) or tar component.

Specific examples of the present contaminating compound include aproduction intermediate which is solid at room temperature such as theCompound (A1), the compound represented by formula (A3) (hereinafterreferred to as “Compound (A3)”), the compound represented by formula(A4) (hereinafter referred to as “Compound (A4)”), the compoundrepresented by formula (A5) (hereinafter referred to as “Compound(A5)”), the compound represented by formula (A8) (hereinafter referredto as “Compound (A8)”), the compound represented by formula (A9)(hereinafter referred to as “Compound (A9)”), the compound representedby formula (A10) (hereinafter referred to as “Compound (A10)”), and theCompound (A11) in the scheme (2) to scheme (5), and a derivative derivedfrom said production intermediate.

In the present invention, the ratio of the crude uracil composition tothe organic solvents (Solvent A and Solvent B) is based on the contentof the pure present uracil compound in the crude uracil composition. Inthe production method of the present invention, the (total) amount ofthe solvents at the time of crystal precipitation of the present uracilcompound is 1.5 to 20 parts by weight, for example 2 to 20 parts byweight per one part by weight of the pure present uracil compound.

As the methods for precipitating a crystal of the present uracilcompound from a solution of the crude uracil composition in the presentinvention, “crystallization by cooling” which comprises cooling saidsolution or “crystallization by poor solvent addition” which comprisesgradually adding a solvent in which the present uracil compound ispoorly dissolved can be used. In both methods, a crystal of the presenturacil compound precipitates at a temperature within the range of −10 to80° C., and preferably −10 to 50° C.

Solvent A and Solvent B may be each one solvent selected from eachgroup, or a mixed solvent of two or more solvents selected from eachgroup. When the crude uracil composition is dissolved in organicsolvents, the crude uracil composition may be added to a mixture ofSolvent A and Solvent B, or the crude uracil composition may bedissolved in Solvent A and then Solvent B may be added thereto.

The ratio of Solvent A to Solvent B is SolventA:Solvent B=10:90 to 99:1,preferably 50:50 to 98:2, and more preferably 60:40 to 98:2 by weightratio at the time when the present uracil compound precipitates.

The present uracil compound precipitated from solvents is filtrated orwashed by a conventional method to separate it from a mother liquor as awet cake. Said wet cake may be dried by a conventional method such asthrough-flow drying using an inert gas such as nitrogen and helium, heatdrying, reduced-pressure drying, and a combined drying method thereof.

Examples of preferable embodiments of the present invention include thefollowing embodiments.

As Solvent A, a solvent selected from the group consisting of1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol,2-methyl-2-propanol, 1-pentanol, 3-methyl-1-butanol, and2-methyl-2-butanol, or a mixture of two or more of them is preferable.2-Propanol is especially preferable.

As Solvent B, a solvent selected from the group consisting of toluene,o-xylene, m-xylene, p-xylene, ethylbenzene, and chlorobenzene, or amixture of two or more of them is preferable. A solvent selected fromthe group consisting of o-xylene, m-xylene, p-xylene, and ethylbenzene,or a mixture of two or more of them is especially preferable.

When Solvent A is 2-propanol, the ratio of Solvent A to Solvent B ispreferably in the range of 2-propanol:Solvent B=80:20 to 98:2, and morepreferably in the range of 85:15 to 98:2 by weight ratio.

The preferable range of total amount of Solvent A and Solvent B variesdepending on the content of the present uracil compound in the crudeuracil composition, and usually 2 to 8 parts by weight is preferable,and 3 to 8 parts by weight is more preferable per one part by weight ofthe pure present uracil compound in the crude uracil composition.

The method for producing the crude uracil composition in the presentinvention is not limited. Specific examples of the crude uracilcomposition include the crude uracil composition produced according tothe method described in the above scheme (2).

The present invention also includes the following method for producing acrystal of the present uracil compound.

A method for producing a crystal of the present uracil compound, themethod comprising

(Step 1) reacting the Compound (A1)

with an alkyl trifluoroacetoacetate;

(Step 2) reacting a crude product comprising the Compound (A3) obtainedin Step 1

with a cyanate in the presence of a protonic acid;

(Step 3) reacting a crude product comprising the Compound (A4) obtainedin Step 2

with a methylating agent in the presence of a base; and

(Step 4) dissolving a crude product comprising the present uracilcompound obtained in Step 3 in organic solvents consisting of a C3-C6alcohol solvent and an aromatic solvent to obtain a solution, andprecipitating a crystal of the present uracil compound from thesolution.

Examples of the alkyl trifluoroacetoacetate in Step 1 include ethyl4,4,4-trifluoroacetoacetate and methyl 4,4,4-trifluoroacetoacetate.

Examples of the cyanate in Step 2 include potassium cyanate and sodiumcyanate. Examples of the protonic acid include organic acids (forexample, acetic acid, propionic acid, butyric acid, benzoic acid,p-toluenesulfonic acid, and methanesulfonic acid), and inorganic acids(for example, hydrochloric acid and sulfuric acid).

Examples of the methylating agent in Step 3 include methyl iodide,methyl bromide, and dimethyl sulfate. Examples of the base includetriethylamine, diisopropylethylamine, potassium carbonate, and sodiumcarbonate.

An example of measurement result of powder X-ray diffraction of crystalsof the present uracil compound obtained by the production method of thepresent invention is shown in FIG. 1. In one embodiment, the crystals ofthe present uracil compound have diffraction peaks as shown in Table 1in powder X-ray diffraction using Cu-Kα radiation.

TABLE 1 2θ value (deg) d value ({acute over (Å)}) Relative height (%)7.4 11.96 32.1 13.8 6.41 72.5 17.7 5.01 100.0 18.5 4.80 52.2 18.7 4.7543.9 19.4 4.57 73.8 21.8 4.07 42.1 22.2 4.00 70.5 22.5 3.96 46.8 24.03.70 24.1 24.9 3.58 28.5 26.2 3.40 23.0 32.6 2.75 48.4

Namely, in one embodiment, crystals of the present uracil compound arecrystals having diffraction peaks mainly at 20=7.4±0.2°, 13.8±0.2°,17.7±0.2°, 18.5±0.2°, 18.7±0.2°, 19.4±0.2°, 21.8±0.2°, 22.2±0.2°,22.5±0.2°, 24.0±0.2°, 24.9±0.2°, 26.2±0.2°, and 32.6±0.2° in powderX-ray diffraction using Cu-Kα radiation.

The conditions for the powder X-ray diffraction are as follows.

(Measurement Conditions)

Device for powder X-ray diffraction: SmartLab (manufactured by RigakuCorporation)X-ray output: CuKα, 45 kV, 200 mASampling interval: 0.02°Scan range: 5° to 50°

EXAMPLES

Hereinafter, the present invention is described in detail by Examples.

Unless otherwise specified, the content in Examples was determined byabsolute calibration curve method using high performance liquidchromatography.

Reference Preparation Example 1

The crude uracil composition was prepared by the production route inscheme (2). A purification step such as silica gel column chromatographywas not carried out also in the first step and the second step, and thecrude product obtained in each step was used as a stating material inthe next step.

Example 1

To a flask were added 126.6 parts by weight of a composition comprisingthe present uracil compound obtained in Reference Preparation Example 1(content of the present uracil compound: 79.0%; comprising 100 parts byweight of the pure present uracil compound), 316.5 parts by weight of2-propanol (manufactured by Kanto Chemical Co., Inc.), and 64.6 parts byweight of xylene (manufactured by Sumitomo Shoji Chemicals Co., Ltd.; amixture of o-xylene, m-xylene, p-xylene, and ethylbenzene), and theresulting mixture was heated to 70° C. under nitrogen atmosphere. Uponconfirmation that there was no insoluble matter, said mixture wasgradually cooled with stirring, and then crystal precipitation wasinitiated at 35° C. After the mixture was further cooled to 0° C., theresulting crystals were separated by filtration. Said crystals werewashed with 253.2 parts by weight of a cooled mixed solvent of2-propanol (the same as above) and xylene (the same as above) with amixture ratio of 5:1 (by weight ratio). After washing, the crystals weredried under reduced pressure to obtain 74.7 parts by weight of thecrystals of the present uracil compound.

The content of the present uracil compound in the resulting crystals ofthe present uracil compound was 96.4%.

The results of analysis of the composition before crystallization andthe resulting crystals by high performance liquid chromatography areshown below.

It could be confirmed that the resulting crystals comprised the presenturacil compound with high purity, and the reduced contents of Compound(A1) and Compound (A3).

TABLE 2 Composition before Area percentage crystallization Resultingcrystals Present uracil 85.6% 97.6% compound Compound (A3)  0.9%  0.1%Compound (A1)  1.1%  0.2% *Measurement conditions of liquidchromatography

Device: Shimadzu LC-20A, HPLC,

Column: SUMIPAX ODS Z-CLUE (3 μm 4.6 mmΦ×100 mm),Mobile phase: Solution A: 0.1% phosphoric acid aqueous solution,Solution B: acetonitrile,

Ratio of Solution B: 10% (0 min)−[30 min]→90% (5 min)→10% (15 min),

Flow rate: 1 mL/min, Temperature: 40° C., Detection wavelength: 274 nm

The following analogous compounds of the present uracil compound orproduction intermediates thereof are added to the crude uracilcomposition, and the composition is subjected to the production methodof the present invention to confirm that the production method of thepresent invention has excellent purification effects also on thecompounds other than Compound (A1) and Compound (A3).

Example 2

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the following Reference Preparation Examples 2 to8, 300 parts by weight of 2-propanol, and 65 parts by weight of xyleneis heated to 70° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with a mixed solvent of 2-propanoland xylene with a mixture ratio of 5:1 (by weight ratio). After washing,the crystals are dried under reduced pressure to obtain the crystals ofthe present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

The methods for producing the compounds added to the crude uracilcomposition described in Example 2 are shown below.

Reference Preparation Example 2

The Compound (A11) (1.0 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.0mmol) were dissolved in toluene 10 ml, and said mixture was heated underreflux with stirring for 3 hours. The reflux solution was passed througha column filled with molecular sieves 5A to adsorb ethanol. The reactionsolution was cooled to obtain the compound represented by formula (A12)(hereinafter referred to as “Compound (A12)”).

To a mixture of the Compound (A12) (0.8 mmol) and acetic acid 3 ml wasadded potassium cyanate (0.8 mmol), and the mixture was stirred at 50°C. for one hour, and additionally stirred at 110° C. for 2 hours. Thereaction mixture was cooled, then poured into water, and extracted withethyl acetate. The organic layers were washed with saturated brine andconcentrated, and the residues were subjected to column chromatographyto obtain the compound represented by formula (A13) (hereinafterreferred to as “Compound (A13)”).

To a mixture of the Compound (A13) (0.5 mmol), potassium carbonate (0.7mmol), and acetonitrile 5 ml was added dimethyl sulfate (0.7 mmol) atroom temperature, and the mixture was stirred at 50° C. for one hour.The reaction mixture was cooled, then poured into water, and extractedwith toluene. The organic layers were washed with saturated brine andconcentrated, and the residues were subjected to column chromatographyto obtain the compound represented by formula (B1) (hereinafter referredto as “Compound (B1)”).

The physical properties of the Compound (B1) are shown below.

¹H-NMR (CD₃CN-D₂O) δ: 7.93 (1H, dd, J=4.9, 1.5 Hz), 7.45 (1H, dd, J=7.6,1.5 Hz), 7.26-7.24 (1H, m), 7.07-7.06 (1H, m), 7.03-7.02 (1H, m),6.93-6.92 (1H, m), 6.33 (1H, s), 4.85-4.84 (2H, m), 4.14 (2H, q, J=7.1Hz), 3.43 (3H, s), 1.19 (3H, t, J=7.1 Hz).

Reference Preparation Example 3

The compound represented by formula (A21) (hereinafter referred to as“Compound (A21)”) (1.0 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.0mmol) are dissolved in toluene 10 ml, and said mixture is heated underreflux with stirring for 3 hours. The reflux solution is passed througha column filled with molecular sieves 5A to adsorb ethanol. The reactionsolution is cooled to obtain the compound represented by formula (A22)(hereinafter referred to as “Compound (A22)”).

To a mixture of the Compound (A22) (0.8 mmol) and acetic acid 3 ml isadded potassium cyanate (0.8 mmol), and the mixture is stirred at 50° C.for one hour, and additionally stirred at 110° C. for 2 hours. Thereaction mixture is cooled, then poured into water, and extracted withethyl acetate. The organic layers are washed with saturated brine andconcentrated, and the residues are subjected to column chromatography toobtain the compound represented by formula (A23) (hereinafter referredto as “Compound (A23)”).

To a mixture of the Compound (A23) (0.5 mmol), potassium carbonate (0.7mmol), and acetonitrile 5 ml is added dimethyl sulfate (0.7 mmol) atroom temperature, and the mixture is stirred at 50° C. for one hour. Thereaction mixture is cooled, then poured into water, and extracted withtoluene. The organic layers are washed with saturated brine andconcentrated, and the residues are subjected to column chromatography toobtain the compound represented by formula (B2) (hereinafter referred toas “Compound (B2)”).

Reference Preparation Example 4

The compound represented by formula (A31) (hereinafter referred to as“Compound (A31)”) (1.0 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.0mmol) are dissolved in toluene 10 ml, and said mixture is heated underreflux with stirring for 3 hours. The reflux solution is passed througha column filled with molecular sieves 5A to adsorb ethanol. The reactionsolution is cooled to obtain the compound represented by formula (A32)(hereinafter referred to as “Compound (A32)”)

To a mixture of the Compound (A32) (0.8 mmol) and acetic acid 3 ml isadded potassium cyanate (0.8 mmol), and the mixture is stirred at 50° C.for one hour, and additionally stirred at 110° C. for 2 hours. Thereaction mixture is cooled, then poured into water, and extracted withethyl acetate. The organic layers are washed with saturated brine andconcentrated, and the residues are subjected to column chromatography toobtain the compound represented by formula (A33) (hereinafter referredto as “Compound (A33)”).

To a mixture of the Compound (A33) (0.5 mmol), potassium carbonate (0.7mmol), and acetonitrile 5 ml is added dimethyl sulfate (0.7 mmol) atroom temperature, and the mixture is stirred at 50° C. for one hour. Thereaction mixture is cooled, then poured into water, and extracted withtoluene. The organic layers are washed with saturated brine andconcentrated, and the residues are subjected to column chromatography toobtain the compound represented by formula (B3) (hereinafter referred toas “Compound (B3)”).

Reference Preparation Example 5

The compound represented by formula (A41) (hereinafter referred to as“Compound (A41)”) (1.0 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.0mmol) are dissolved in toluene 10 ml, and said mixture is heated underreflux with stirring for 3 hours. The reflux solution is passed througha column filled with molecular sieves 5A to adsorb ethanol. The reactionsolution is cooled to obtain the compound represented by formula (A42)(hereinafter referred to as “Compound (A42)”).

To a mixture of the Compound (A42) (0.8 mmol) and acetic acid 3 ml isadded potassium cyanate (0.8 mmol), and the mixture is stirred at 50° C.for one hour, and additionally stirred at 110° C. for 2 hours. Thereaction mixture is cooled, then poured into water, and extracted withethyl acetate. The organic layers are washed with saturated brine andconcentrated, and the residues are subjected to column chromatography toobtain the compound represented by formula (A43) (hereinafter referredto as “Compound (A43)”).

To a mixture of the Compound (A43) (0.5 mmol), potassium carbonate (0.7mmol), and acetonitrile 5 ml is added dimethyl sulfate (0.7 mmol) atroom temperature, and the mixture is stirred at 50° C. for one hour. Thereaction mixture is cooled, then poured into water, and extracted withtoluene. The organic layers are washed with saturated brine andconcentrated, and the residues are subjected to column chromatography toobtain the compound represented by formula (B4) (hereinafter referred toas “Compound (B4)”).

Reference Preparation Example 6

The Compound (A4) (1.0 mmol) was dissolved in toluene 5 ml, and to themixture was added dropwise a solution of diazomethane (1.0 mmol) intoluene 1 ml at room temperature. Then, the reaction solution was pouredinto water, and extracted with toluene. The organic layers were washedwith saturated brine and concentrated. The residues were subjected tosilica gel chromatography to obtain the compound represented by formula(59) (hereinafter referred to as “Compound (B9)”).

LC/MS (ESI-MS(posi)): 518[M+H]⁺

Reference Preparation Example 7

To a mixture of the Compound (A4) 0.71 g, toluene 50 mL, and methanol 10mL was added dropwise a solution of trimethylsilyldiazomethane in hexane(0.6 mol/L) 4.7 mL under ice-cooling. The mixture was stirred at thesame temperature for 30 minutes, and then acetic acid was added theretountil bubbling stopped. The reaction mixture was concentrated, and thenthe resulting residues were subjected to silica gel chromatography toobtain the Compound (B9) 0.13 g.

¹H-NMR (CDCl₃) δ: 7.91 (1H, dd, J=5.0, 1.6 Hz), 7.39-7.34 (2H, m),6.97-6.93 (2H, m), 6.53 (1H, s), 5.02 (1H, d, J=16.0 Hz), 4.84 (1H, d,J=16.0 Hz), 4.15 (2H, q, J=7.1 Hz), 3.94 (3H, s), 1.24 (3H, t, J=7.1Hz).

Reference Preparation Example 8

The Compound (A1) (1.0 mmol) and triethylamine (1.5 mmol) were dissolvedin tetrahydrofuran 8 ml, and acetyl chloride (1.5 mmol) was addedthereto at room temperature. Said mixture was stirred at 40° C., andthen the reaction solution was poured into water. The resulting mixturewas extracted with ethyl acetate, and the organic layers were washedwith saturated brine and concentrated. The resulting residues weresubjected to column chromatography to obtain the compound represented byformula (B10) (hereinafter referred to as “Compound (B10)”)

LC/MS (ESI-MS (posi)): 383 [M+H]⁺

Example 3

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,169 parts by weight of 2-propanol, and 4 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with 2-propanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Example 4

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,160 parts by weight of 2-propanol, and 18 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with 2-propanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Example 5

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,255 parts by weight of 2-propanol, and 28 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with 2-propanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Example 6

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,141 parts by weight of 2-propanol, and 36 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with 2-propanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Example 7

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,256 parts by weight of 2-propanol, and 29 parts by weight of toluene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with 2-propanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Example 8

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,255 parts by weight of 1-butanol, and 27 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with 1-butanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Example 9

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,255 parts by weight of 2-propanol, and 29 parts by weight ofchlorobenzene is heated to 60° C. Said mixture is gradually cooled toinitiate crystal precipitation at a temperature of 50° C. or less. Afterthe mixture is further cooled to 0° C., the resulting crystals areseparated by filtration. The crystals are washed with 2-propanol of 0°C. After washing, the crystals are dried under reduced pressure toobtain the crystals of the present uracil compounds.

The resulting crystals are analyzed to confirm that they comprise thepresent uracil compound with high purity, and the reduced contents ofcompounds other than the present uracil compound.

Comparative Example 1

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,271 parts by weight of ethanol, and 11 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with ethanol of 0° C. After washing,the crystals are dried under reduced pressure to obtain the crystals ofthe present uracil compounds.

Comparative Example 2

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,281 parts by weight of ethanol, and 2 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with ethanol of 0° C. After washing,the crystals are dried under reduced pressure to obtain the crystals ofthe present uracil compounds.

Comparative Example 3

A mixture of the crude uracil composition (comprising 100 parts byweight of the pure present uracil compound) comprising 0.1 to 1% of eachcompound prepared in the above Reference Preparation Examples 2 to 8,270 parts by weight of methanol, and 10 parts by weight of xylene isheated to 60° C. Said mixture is gradually cooled to initiate crystalprecipitation at a temperature of 50° C. or less. After the mixture isfurther cooled to 0° C., the resulting crystals are separated byfiltration. The crystals are washed with methanol of 0° C. Afterwashing, the crystals are dried under reduced pressure to obtain thecrystals of the present uracil compounds.

INDUSTRIAL APPLICABILITY

A crystal of the present uracil compound with high purity can beobtained by the production method of the present invention.

1. A method for producing a crystal of a uracil compound represented by formula (1)

wherein the method comprises dissolving a composition comprising the uracil compound in organic solvents consisting of a C3-C6 alcohol solvent and an aromatic solvent to obtain a solution, and precipitating a crystal of the uracil compound from the solution.
 2. The method for producing a crystal of a uracil compound according to claim 1, wherein the crystal of the uracil compound is precipitated by cooling a solution of a crude composition.
 3. The method for producing a crystal of a uracil compound according to claim 1, wherein the C3-C6 alcohol solvent is a solvent selected from the group consisting of 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 3-methyl-1-butanol, and 2-methyl-2-butanol, or a mixture of two or more of them, and the aromatic solvent is a solvent selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, and chlorobenzene, or a mixture of two or more of them.
 4. The method for producing a crystal of a uracil compound according to claim 1, wherein a weight ratio of the C3-C6 alcohol solvent to the aromatic solvent is 50:50 to 98:2.
 5. A method for producing a crystal of a uracil compound represented by formula (1)

the method comprising Step 1: reacting a compound represented by formula (A1)

with an alkyl trifluoroacetoacetate; Step 2: reacting a crude product comprising a compound represented by formula (A3) obtained in Step 1

with a cyanate in the presence of a protonic acid; Step 3: reacting a crude product comprising a compound represented by formula (A4) obtained in Step 2

with a methylating agent in the presence of a base; and Step 4: dissolving a crude product comprising the uracil compound represented by formula (1) obtained in Step 3 in organic solvents consisting of a C3-C6 alcohol solvent and an aromatic solvent to obtain a solution, and precipitating a crystal of said uracil compound from the solution. 